1. Field of the Invention
This invention relates to an efficient three-step process for the preparation of 7-alkyl-10-hydroxy-20(S)-camptothecin from the readily available natural product, 20(S)-camptothecin. The invention also demonstrates a novel intermediate useful in this synthesis.
2. Description of the Related Art
Camptothecin derivatives have shown significant cytotoxic activity and several have been developed into useful pharmaceuticals. Specifically Irinotecan (Campto) has shown excellent activity toward colon-rectal cancers and is widely marketed. It shows considerable advantage over other camptothecin derivatives in that it is water soluble.
Irinotecan is prepared in several steps from the key intermediate, 7-ethyl-10-hydroxy-20(S)-camptothecin. Considerable effort has been expended to introduce both the 10-hydroxy and the 7-ethyl functionality into the camptothecin molecule. Therefore, while there is some prior art associated with each of these individual groups, there is very little knowledge on introduction of both these functionality simultaneously into the molecule.
Sawada (Chem. Pharma. Bull., 39(12), 3183(1991) demonstrates the synthesis of 7-ethyl-10-hydroxy-20(S)-camptothecin through the synthesis of 7-ethyl-20(S)-camptothecin by known means, the subsequent formation of an N-oxide and the photochemical rearrangement to provide 7-ethyl-10-hydroxy-20(S)-camptothecin. However, this synthesis suffers considerably from the insolubility of 7-ethyl-20(S)-camptothecin in suitable solvents and thus only small quantities can be prepared.
10-Hydroxy-20(S)-camptothecin has been prepared by the hydrogenation of 20(S)-camptothecin to 1,2,6,7-tetrahydro-20(S)-camptothecin and subsequent oxidation. Thus U.S. Pat. No. 5,734,056 describes the preparation through the hydrogenation of 20(S)-camptothecin to 1,2,6,7-tetrahydro-20(S)-camptothecin followed by the oxidation with iodosobenzene derivatives specifically esters such as iodobenzenediacetate. Japanese pat. No. 59-5188 discloses the hydrogenation of camptothecin followed by oxidation with agents such as CAN(cerium (IV) ammonium nitrate, chromic acid, potassium permanganate, Fremy's salt. Similarly, Sawada, et. al. (Chem. Pharm. Bull. 39(120)3183, 1991) describes a reduction and oxidation with lead tetraacetate. In all these cases, the use of a 7-substituted derivative has not been demonstrated.
The preparation of 7-ethyl-20(S)-camptothecin has been demonstrated previously through the Fenton reaction by employing 20(S)-camptothecin and propionaldehyde with ferrous sulfate and sulfuric acid.
Therefore there is a need for an efficient synthesis of 7-ethyl-10-hydroxy-20(S)-camptothecin which can be used in commercial scale.